Infectious complications in patients with recurrent hepatitis C virus (HCV) hepatitis after liver transplantation were prospectively assessed and compared with those of all other liver transplant recipients without HCV hepatitis operated on during the same period. Major infections occurred in 64% (14/22) of the patients with recurrent HCV hepatitis versus 38% (30/78) of all other patients (P = 0.04). Patients with recurrent HCV hepatitis had significantly more episodes of major infections (mean 1.45 episodes/patient vs. 0.51 episodes/patients, P = .003) and were more likely to have recurrent episodes of major infections (45%, 10/22, vs. 10%, 8/78, P = 0.005) than all other patients, respectively. The incidence of major bacterial infections was not higher in patients with recurrent HCV hepatitis (41% vs. 28%, P = NS); however, incidence of fungal infections was higher (18% vs. 6%, P = 0.10) and incidence of cytomegalovirus disease was significantly higher (32% vs. 9%, P = 0.012) in patients with recurrent HCV hepatitis as compared with all other patients. Late infections, i.e., those occurring > 6 months after transplantation, were significantly higher in patients with recurrent HCV (27% vs. 6%, P = 0.011). Rejection episodes occurring within 6 months after transplantation were higher in patients with recurrent HCV hepatitis (P = 0.09); however, the intensity of immunosuppression as measured by corticosteroid boluses and cycles was not significantly different in these patients when compared with all other patients. Aminotransferase levels were significantly higher in patients with HCV recurrence than in other patients. We conclude that recurrent HCV hepatitis after liver transplantation is associated with a high incidence of infections due to pathogens associated with depressed cell-mediated immunity. Future studies should assess the exact nature of the suppressive effect on host defense in recurrent HCV hepatitis.